Dual-Treatment Approach To Parkinson's Disease

Increasingly, treatments are being developed that combine the use of devices and medication.

Thomas Morrow, MD

More often than not, advances in medical technology can make the job of the medical and pharmacy director highly complicated. To manage their patients successfully, clinicians have to develop comprehensive processes that integrate the medical and pharmacy benefit, choosing the best way to allocate precious medical and pharmacy dollars. Complicating the management picture even more is science fiction technology.

This is especially true for Parkinson's disease, which can be treated medically, but for which novel technology is fast emerging.

Now available

A novel approach using electrical stimulation to treat Parkinson's disease is now available. Science fiction movies have long shown disturbing images of various implants controlling the brain of an unsuspecting individual, and as with many other advances, science fiction has predicted reality in this arena.

But this advance is not meant to control the will or activities of an individual, but to control the chronic, disabling tremors associated with Parkinson's disease.

Deep brain stimulation (DBS) uses surgically implanted, tunable, battery-operated neurostimulators to deliver electrical signals to targeted areas of the brain to block the abnormal nerve signals that cause the tremor associated with Parkinson's disease. These devices are manufactured by Advanced Neuromodulation Systems and by Medtronic. The Medtronic product has received FDA approval.

The DBS system consists of a "pacemaker-like" neurostimulator about the size of a pocket watch, the lead, and the extension to the lead. The lead is placed into the area of the brain responsible for movement, which is identified by MRI and three-dimensional imaging. It is connected to the extension that goes to the neurostimulator, and is typically surgically implanted in the chest or abdominal wall. Prior neurosurgical procedures, first developed in the 1960s, intentionally destroyed parts of the globus pallidus to aid Parkinson's disease patients. Deep brain stimulation does not destroy brain tissue, making it a reversible surgical therapy — important if other, more precise and/or advanced therapies, are developed.

With DBS, the patient with Parkinson's disease typically experiences a significant reduction in symptoms and can decrease the medication, while reducing the common long-term side effects. DBS is adjustable: Multiple electrodes are typically placed on the patient to allow "tuning" of the effects. Because the brain has two sides, some patients will require two separate DBS units. If two stimulators are needed, the surgery is typically done on two separate occasions to prevent complications and to evaluate the results of each surgery individually.

Usually, the goal of DBS is to control tremors of the arm. Others, such as head and body tremors, can be helped, but are not typical targets. Secondary goals are reduction of the dyskinesias associated with the medical therapy of Parkinson's disease. It is important to understand that DBS does not help gait or balance and does not improve vision or strength.

Key issues with neurostimulation include:

The device can be turned off at night.

The response to the stimuli can take months to reach a therapeutic maximum.

No long-term damage to the brain has been observed.

The target population may be as high as 15 percent of Parkinson's disease patients.

Managed care implications

This surgery is highly specialized, very expensive, and should be conducted at centers with specialists in movement disorders. The differential diagnosis must rule out focal lesions in the basal ganglia, including vascular insults, and tumors. The patient must still have enough function to benefit, failure of medical therapy should be established, and the patient should be mobile and communicative to produce maximal benefit. Remember that most patients will remain on drug therapy.

DBS and the continued developments in pharmaceuticals and biotechnology continue to demonstrate the acute need for MCOs to integrate their medical and pharmacy management programs. Do you have a cross-functional committee or process by which you can monitor and manage disparate treatment options such as devices and medications in a concerted way? Do you have benefit plans that encourage the excessive use of a more expensive technology over a less expensive older one just because of your copayment structure? Do you have the internal educational capability to maintain the competency of your case managers as they receive inquiries about diseases that can be treated in a variety of ways? If not, this is the time to prepare, because the future will bring more approaches that combine pharmaceuticals and devices. Additional indications are being pursued for deep brain stimulation, including treatment-resistant chronic depression, Tourette Syndrome, and migraine.

What it is

Parkinson's disease, first described in 1817 by James Parkinson in his Essay on the Shaking Palsy, is an idiopathic, extrapyramidal neurodegenerative disease that affects the substantia nigra in the basal ganglia. It is characterized by the loss of dopaminergic neurons. Dopamine is a neurotransmitter synthesized at the presynaptic terminal of the neuron.

The enzyme tyrosine hydroxylase converts the amino acid tyrosine to dopa, which is then converted by dopa decarboxylase to dopamine. Dopamine then crosses the synapse to activate the dopamine receptor, after which the dopamine is metabolized by monoamine oxidase and catechol-O-methyltransgerase (COMT) to inactive metabolites. These pathways are important to understand as most of the current therapy involves these enzymes to one extent or another.

The diagnosis of Parkinson's disease is basically a clinical one, as there is currently no simple diagnostic test for this disorder. The diagnosis is based upon having two of the three main features of Parkinson's disease present: bradykinesia (including akinesia or hypokinesia), rigidity, and resting tremor. The low frequency (4–6 Hz) resting tremor common to Parkinson's disease affects primarily the digits, hands, arms, head, and lips and decreases or ceases during voluntary movement and while sleeping. Although the disease was first documented nearly 200 years ago, the biochemical pathways were not identified for nearly a century and a half.

The exact cause of this disease is unknown. Although there is a genetic predisposition to Parkinson's disease, the majority of patients have not been found to have a directly related genetic trait.

The balance

Normally functioning dopamine-secreting cells in the substantia nigra act to stimulate the direct pathway of movement. These cells also inhibit the indirect pathway of movement. The balance of these pathways is a key mechanism by which the body produces smooth coordinated movement. With Parkinson's disease, the dopamine-secreting cells deteriorate, leading to an increased effect of the indirect pathway of movement. The result is the typical bradykinesia characteristic of Parkinson's disease. Symptoms typically occur only upon loss of about 50–80 percent of dopamine secretion. Parkinson's disease is a progressive disease, hence the level of dopamine continues to deteriorate and symptoms progress. Parkinson's disease causes more than just a movement disorder. It also is associated with sleep disturbances, dizziness, depression, speech disorders, stooped posture, constipation, fatigue, sexual dysfunction, and altered sense of smell.

Medical therapy

Current medical therapy consists of replacing or mimicking the effects of dopamine.

Current medical treatment options

Antivirals (amantadine)

Anticholinergics

MAO-B inhibitors

Dopamine agonists

Levodopa/carbidopa

COMT inhibitors (adjunctive therapy)

The oldest medication, levodopa (L-dopa), was first introduced more than three decades ago. L-dopa is converted in the brain to dopamine. This replenishes the diminished natural dopamine. Because of a naturally occurring intravascular enzyme, L-dopa is always combined with an enzyme inhibitor, carbidopa, to prevent the circulating L-dopa from being destroyed prior to entering the brain parenchyma. Within four to five years of starting L-dopa, the majority of patients begin to experience dyskinesias as well as fluctuations in the effects of the drug that can actually lead to freezing of all movement.

Because of the considerable limitations of dopamine, other termed dopamine agonists have been developed that do not need to be modified in the brain. These drugs act directly on the dopamine receptor.

Dopamine agonists

Bromocriptine (Parlodel)

Pergolide (Permax)

Pramipexole (Mirapex)

Ropinirole (Requip)

Apomorphine

Another approach is to raise the level of dopamine at the synapse by inhibiting the enzymatic degradation of dopamine. The two basic pathways to dopamine degradation are MAO and COMT. Both of these pathways are targets for current therapy. The COMT inhibitors include encatopone (Comtan) and tolcapone (Tasmar). The MAO-B inhibitors include selegiline (Eldepryl) and the currently FDA-approved and soon-to-be-released rasagiline (Agilect). Interestingly, the majority of the metabolites of selegiline are methamphetamine and amphetamine, both of which are neurotoxic and responsible for the side effects of insomnia, hallucinations, and agitation. The latest product, rasagiline, which is expected to be approved this fall, is metabolized to aminoindan with no sympathomimetic activities.

Finally, amantadine and anticholinergic agents such as biperiden HCL (Akineton), benztropine mesylate (Cogentin), procyclidine (Kemadrin) and trihexyphenidyl (Artane) are used, but they have considerable side effects, as expected.

The treatment of Parkinson's disease is complicated. Patients may benefit from a dual approach that uses medical therapy with new innovative treatment systems.

Thomas Morrow, MD, is president of the National Association of Managed Care Physicians and vice president and medical director of Matria Health Care. He has 20 years of managed care experience at the payer or health plan level.
Dr. Morrow discloses that he has received honoraria or other financial benefit during the last three years from the following commercial companies: Amgen, Amylin Pharmaceuticals, AstraZeneca, Biogen Idec, Centocor, Galderma, Genentech, GlaxoSmithKline, Johnson & Johnson, Merck, Novartis, Novo Nordisk, Pfizer, Procter & Gamble, Q-Med, Sanofi-Aventis, Teva Pharmaceuticals Industries, UCB, and Wyeth.